The immune system consists of innate and adaptive or acquired immune responses. The innate immune response is immediate and includes physical, chemical or mechanical barriers, along with cells that are the first to the site of infection or damage, the neutrophils, followed by dendritic cells and macrophages, all of which can engulf or phagocytize potentially harmful pathogens or debris. The phagocytes also are involved in the transition between innate and acquired immunity by processing and loading their engulfed material, loading the fragments into molecules that are embedded in the lysosomal/endosomal compartments, the Major and Minor Histocompatibility Complex (MHC) encoded molecules of T cell immunity. MHC is believed to be the genetic complex responsible for the rejection. The MHC genes, also known as immune response or IR genes, and their protein products are responsible for all graft rejection. There are two types of MHC molecules: MHC class I and MHC class II. All nucleated cells express cell surface MHC class I. A subset of specialized cells express class II MHC. Included in the specialized, professional antigen-presenting cells (APCs) are B cells, macrophages, microglia, dendritic cells, and Langerhans cells among others.
B lymphocytes are specialized cells with specific receptors that are antigen specific that ultimately secrete a soluble copy of its membrane-bound antigen receptor. Once antigen has been bound by the antigen receptor on the B cell, the antigen and its receptor are engulfed into an endosomal compartment. This compartment fuses with another compartment known as the lysosome. The B cell is very efficient at breaking down antigens into smaller parts and loading the parts into MHC class II in the lysosome. The MHC is then trafficked to the cell surface where the B cell can effectively “show” the antigen to a CD4+ T cell. The activated CD4 cell is also called a helper cell and there are two major categories, Th1 and Th2.
The MHC molecules are tightly protected in the endosomal/lysosomal compartments to insure that only antigens for which we need a response get presented to T cells. MHC class II molecules, prior to antigen loading, are associated with a peptide fragment derived from a molecule called invariant chain, also known as CD74. The invariant chain is associated with MHC class II (and recently shown to be associated with certain MHC class I molecules) prior to antigen loading into the antigen binding grooves of the MHC molecules. As antigen is processed, the invariant chain gets cleaved by proteases within the compartment. First an end piece is removed, and then another known as CLIP (class II invariant chain associated peptide). CLIP fills the groove that will ultimately hold the antigen until the antigen is properly processed. For a detailed review of the invariant chain, including CLIP, see Matza et al. (2003), incorporated herein in its entirety. Despite the fact that this “chaperone” role for invariant chain and CLIP has been identified, the full impact of these molecules on immune signaling and activation has yet to be determined.